Short Communication Metabolism of Quetiapine by CYP3A4 and CYP3A5 in Presence or Absence of Cytochrome B5

The antipsychotic drug quetiapine is extensively metabolized by CYP3A4, but little is known about the possible influence of the polymorphic enzyme CYP3A5. This in vitro study investigated the relative importance of CYP3A4 and CYP3A5 in the metabolism of quetiapine and compared the metabolic pattern by the two enzymes, in the presence or absence of cytochrome b5. Intrinsic clearance (CLint) of quetiapine was determined by the substrate depletion approach in CYP3A4 and CYP3A5 insect cell microsomes with or without coexpressed cytochrome b5. Formation of the metabolites quetiapine sulfoxide, N-desalkylquetiapine, O-desalkylquetiapine, and 7-hydroxyquetiapine by CYP3A4 and CYP3A5 were compared in the different microsomal preparations. CLint of quetiapine by CYP3A5 was less than 35% relative to CYP3A4. CLint was higher (3-fold) in CYP3A4 microsomes without cytochrome b5 compared with CYP3A4 microsomes with coexpressed cytochrome b5, whereas in CYP3A5 microsomes CLint was similar for both microsomal preparations. Metabolism of quetiapine by CYP3A5 revealed a different metabolic pattern compared with CYP3A4. The results indicated that O-desalkylquetiapine constituted a higher proportion of the formed metabolites by CYP3A5 compared with CYP3A4. In conclusion, the present study indicates that CYP3A5 is of minor importance for the overall metabolism of quetiapine, regardless of the presence of cytochrome b5. However, a different metabolic pattern by CYP3A5 compared with CYP3A4 could possibly result in different pharmacological and/or toxicological effects of quetiapine in patients expressing CYP3A5. Quetiapine, a dibenzothiazepine derivative, is an atypical antipsychotic drug used for the treatment of schizophrenia and acute episodes of mania. Recently, the U.S. Food and Drug Administration also approved quetiapine for the treatment of depressive episodes associated with bipolar disorder. Quetiapine is extensively metabolized in the liver by the cytochrome P450 (P450) system, primarily by CYP3A (Grimm et al., 1997, 2006). The major metabolic pathways of quetiapine are through sulfoxidation, Nand O-dealkylation, and, to a lesser degree, through 7-hydroxylation (Grimm et al., 1997) (Fig. 1). The pharmacologically inactive metabolite quetiapine sulfoxide is considered to be the main metabolite of quetiapine (DeVane and Nemeroff, 2001), whereas the most important active metabolite seems to be N-desalkylquetiapine (McIntyre et al., 2007). Studies indicate that N-desalkylquetiapine, unlike the parent compound, is a potent inhibitor of the noradrenergic transporter and has partial agonist activity at the 5-hydroxytryptamine 1A receptor (Goldstein et al., 2007; Jensen et al., 2008). In addition, N-desalkylquetiapine was found to possess antidepressive-like activity in a mouse model (Jensen et al., 2008). This suggests that the antidepressive activity of quetiapine is, at least partly, mediated by N-desalkylquetiapine. The active metabolite 7-hydroxyquetiapine is formed by CYP2D6 in addition to by CYP3A (Grimm et al., 2006). Because of the low plasma concentration of this metabolite (Gefvert et al., 1998), genetic polymorphism in CYP2D6 is unlikely to be of importance for the in vivo metabolism of quetiapine. CYP3A4 and CYP3A5 comprise the two main CYP3A isoforms in adults. The individual variability in phenotype is substantial for both enzymes, but this variability is linked to genetic polymorphism only for CYP3A5 (Westlind-Johnsson et al., 2003). CYP3A5 is expressed in approximately 10 to 30% of whites, 30% of Japanese, and 60% of African Americans (Kuehl et al., 2001; Burk and Wojnowski, 2004). The relative contribution of CYP3A5 to total hepatic CYP3A protein differs, but in some individuals CYP3A5 can constitute more than 50% of total CYP3A (Kuehl et al., 2001; Lin et al., 2002; WestlindJohnsson et al., 2003). Individuals expressing CYP3A5 may have higher clearance and lower bioavailability of CYP3A substrates compared with individuals not expressing CYP3A5 (Kuehl et al., 2001). This has been demonstrated for both the immunosuppressive drug tacrolimus and for several HMG-CoA reductase inhibitors (statins) where patients expressing CYP3A5 need higher drug dosages to reach target serum concentration or to achieve sufficient lipid-lowering response, respectively (Hesselink et al., 2003; Zheng et al., 2003; Goto et al., 2004; Kivisto et al., 2004; Ferraresso et al., 2007). CYP3A4 and CYP3A5 overlap in substrate specificity, but the relative importance of CYP3A4 and CYP3A5 in overall CYP3Amediated metabolism differs between substrates (Lamba et al., 2002). The role of CYP3A5 in the metabolism of quetiapine is sparsely known. Therefore, the objective of this in vitro study was to investigate the relative importance of CYP3A4 and CYP3A5 in the metabolism of quetiapine and to compare the metabolic pattern by the two enzymes. Because the presence of cytochrome b5 (cyt b5) in the incubation assay has been shown to affect the metabolism of many drugs via CYP3A4 and CYP3A5 in vitro (Yamaori et al., 2003), the effect of cytochrome b5 on quetiapine metabolism was also examined. Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.108.023291. ABBREVIATIONS: P450, cytochrome P450; cyt b5, cytochrome b5; CLint, intrinsic clearance. 0090-9556/09/3702-254–258$20.00 DRUG METABOLISM AND DISPOSITION Vol. 37, No. 2 Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics 23291/3433030 DMD 37:254–258, 2009 Printed in U.S.A. 254 at A PE T Jornals on Jne 3, 2017 dm d.aspurnals.org D ow nladed from